By discovering the atomic structure of a key human enzyme, researchers at The University of Texas at Austin have pointed the way toward designing anti-HIV drugs with far less toxic side effects.

Their work was published this week in Cell.

“Many anti-HIV drugs are designed to stop the process of DNA replication,” says Dr. Whitney Yin, assistant professor of chemistry and biochemistry. “That turns out to be a great thing to do to help cure virus infections, because it stop the processes of viral replication.

“At the same time, however, when you target such a critical process in viruses, you may also target human enzymes that perform similar functions in normal cells, and this is what causes harmful drug side effects.”

Yin and her graduate student, Young-sam Lee, have solved the atomic structure of an enzyme, known as Pol ? (pol gamma), that is responsible for DNA replication in human mitochondria.

When mitochondria are working normally, they produce most of the energy that sustains human cells. When pol gamma comes into contact with certain anti-retroviral drugs, however, it can incorporate the drug into mitochondrial DNA, and thus interfere with the normal replication process. This interferes with the ability of mitochondria to function. The consequences can range from simple nausea to bone marrow depletion to organ failure.

“Patients who are taking this class of anti-HIV drugs have suffered these drug toxicities for a long time,” says Yin. “Dosages and combinations of drugs can be chosen so they don’t kill you, but they still can’t be used at their most effective concentrations against HIV. However, in large part because combination therapies have become more successful and patients are living longer, toxicity has become more of an issue than before.”

Although it’s been known for some time that pol gamma is responsible for mediating the toxicity of the drugs, Yin says, it has been difficult to design a drug that can distinguish between HIV and pol gamma without knowing the structure of pol gamma. With the structures of both pol gamma and HIV known, the differences between the two can be exploited in the design of new drugs that will be more selective (and thus less toxic) against HIV.

“This is a unique opportunity for drug design,” says Yin. “Now you have two pictures side by side. You have the viral target protein and the human protein. You know not to do anything in this region where the two proteins are similar, but rather focus in areas where they’re different.”

In addition to its relevance to anti-HIV drug design, Yin’s research is also helping to explain how mutations in pol gamma lead to various degenerative diseases, including epilepsy, encephalopathy and Alpers’ syndrome (a fatal childhood disease leading to brain and liver failure).

The National Institutes of Health (NIH) and the Welch Foundation funded the work.

Source:
Whitney Yin

University of Texas at Austin

ChemDiv, Inc. (ChemDiv) of San Diego has proudly announced that its wholly owned subsidiary Chemical Diversity Research Institute (CDRI ) of Moscow, Russia, has been chosen by Viriom Ltd. ( Viriom) of Moscow, Russia as a service partner in developing innovative HIV compounds. The program includes pre-clinical and clinical studies, which are expected to begin in 2010.

Viriom has recently signed the license agreement with Roche. Under the terms of this agreement Roche granted Viriom development and commercialization rights for potential novel HIV/AIDS medicine in Russia, Ukraine, Belarus and Kazakhstan. Subject to performance of the program Viriom will also receive license fees, development milestones and royalties on worldwide sales.

Vadim Bichko, Vice President Virology at ChemDiv, Inc., said: “We are excited about this new collaboration with Viriom and Roche. These novel HIV inhibitors have shown excellent antiviral properties in vitro, good bioavailability, PK and safety profiles, as well as a high genetic barrier to resistance. Based on pre-clinical studies to date, these molecules have the potential to become best in class HIV drugs.”

About VIRIOM

VIRIOM Ltd. is an innovative company that was established in 2009 to develop targeted medicines for HIV/AIDS. Basis is the Center of High Technologies ChemRar to which VIRIOM is affiliated. VIRIOM is planning to conduct research and clinical trials in Russia using the experience and knowledge of Russian scientists. Chemical Diversity Research Institute, Prudentas Ltd. and Drug Technologies Ltd.of ChemRar Hi Tech Center (ChemRar) as well as Moscow City Center for prevention and treatment of HIV/AIDS were selected as partners in this program.

About ChemDiv, Inc.

ChemDiv collaborates with pharmaceutical and biotech partners by enabling them to accelerate their R&D programs to higher value clinical inflection points. ChemDiv provides integrated drug discovery and early clinical development, extracting value from potential therapeutic candidates via rapid, streamlined outcomes and effective use of capital.

ChemDiv is the only vertically and horizontally integrated discovery and development CRO headquartered in San Diego, CA, with: unique access to the Eastern European emerging pharma market; rational drug design and medicinal chemistry in a broad range of therapeutic areas of target classes; world’s largest small molecule inventory; working with 20 top pharma and 100 top biotechs in all major markets.

With its successful 20 year business record in life sciences and over 500 research associates equivalent employed globally, ChemDiv has successfully prosecuted fully integrated programs from target to Proof of Concept (POC) and market registration.

About Chemical Diversity Research Institute.

CDRI is a contract research organization focused on pre-clinical and clinical R&D. CDRI sees its mission in enabling discovery and development of innovative therapies for unmet needs utilizing the highest expertise and innovation potential of Russian scientists with integrated external R&D solutions of Discovery outSource™ platforms. Discovery outSource™ platform solutions cover the complete range of disciplines from identification of a biological target (protein expression, assay development etc.); to clinical drug candidates (ADME/DMPK, toxicity and safety studies, in vivo animal models, drug formulation etc.); to drug development candidate (Phase I to Phase IV).

Source
ChemRar Hi Tech Center

An Austin, Texas orthopaedic surgeon has agreed that he and his staff will not deny or withhold medically appropriate treatment from patients solely because they are HIV-positive, according to the U.S. Department of Health and Human Services (HHS). Under a settlement agreement reached with HHS’ Office for Civil Rights (OCR), the surgeon, whose practice group sees an average of 200 patients per week, will establish a non-discrimination policy, make reasonable modifications to his procedures to avoid discrimination against individuals living with HIV/AIDS, receive comprehensive training, implement patient grievance procedures, and inform patients of their right to file a complaint with OCR.

The settlement agreement will bring the surgeon into compliance with Section 504 of the Rehabilitation Act of 1973 (Section 504). Section 504 requires recipients of federal financial assistance (often health care providers reimbursed by Medicaid) to ensure that qualified individuals with disabilities, including those with HIV/AIDS, have equal access to their programs, services or activities.

“Medical providers covered by Section 504 have a legal obligation to provide medically appropriate services to qualified individuals with disabilities,” said OCR Director Georgina Verdugo. “Under Section 504, medical providers may not deny or withhold medically appropriate treatment, as determined by reasonable medical judgment given the current state of medical knowledge, solely on the basis of a patient’s HIV status. As our investigation, violation finding, and settlement of this Austin case demonstrate, OCR is committed to ensuring that all qualified individuals with disabilities — including those with HIV/AIDS — are afforded equal access to quality medical services.”

The prevalence of HIV/AIDS in the greater Austin area has increased 63 percent since 2000 and is the third highest in the State of Texas, according to a Dec. 31, 2007, report of the Austin/Travis County Health and Human Services Department. Over 1.5 million people reside in the Austin Transitional Grant Area (TGA), which was established under the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act and includes Bastrop, Caldwell, Hays, Travis and Williamson counties. Medicaid enrolls 7.3 percent of the Austin TGA and nearly 25 percent of the population does not have public or private health insurance. For individuals living with HIV/AIDS in the Austin TGA, 49.9 percent are Caucasian, 24.8 percent are Latino, and 24.2 percent are African-American.

The settlement with the Austin orthopaedic surgeon was negotiated following OCR’s investigation of an administrative complaint filed by a Latino male patient living with HIV. The patient, a Medicaid beneficiary, sought medical treatment for a knee injury and informed the surgeon of his HIV status. The surgeon contended that if he performed surgery on the man’s knee (a bone-tendon-bone Reconstruction), blood would splatter and possibly expose him to HIV disease. Due to the patient’s HIV status, the Austin surgeon referred the patient to another surgeon located over 200 miles away.

OCR found that the Austin surgeon violated Section 504 by refusing to perform the surgery and instead referring the patient to another surgeon. In making its determination, OCR relied on the expert opinion of a physician and medical epidemiologist from the National Center for Infectious Diseases at HHS’ Centers for Disease Control and Prevention (CDC). The CDC expert opined that practicing effective “universal precautions” — medical guidelines for the prevention and management of exposures to blood and body fluids — would have been the appropriate course of action for the Austin surgeon, instead of refusing to perform the surgery.

“At CDC, we are committed to ensuring that HIV/AIDS treatment decisions are based on the latest scientific evidence,” said Thomas R. Frieden, M.D., M.P.H., director of the CDC. “We appreciate the opportunity to provide expert consultation on the risks of HIV exposure in health care settings.”

Under the settlement, the Austin surgeon will receive comprehensive training on current HIV treatment protocols, universal precautions, and infection control procedures. The Texas/Oklahoma AIDS Education and Training Center, funded by HHS’ Health Resources and Services Administration (HRSA), has offered to provide the Austin surgeon with interactive, hands-on training and on-site clinical consultation. HRSA’s AIDS Education and Training Centers (AETC) Program supports a network of 11 regional centers (and more than 130 local performance sites) that conduct targeted, multi-disciplinary, free and low-cost training to health care professionals working with existing and emerging populations affected by HIV.

HRSA Administrator Mary Wakefield, Ph.D., R.N., stated, “We are pleased that one of our AIDS Education and Training Center grantees has offered this service to a health care professional as part of an OCR settlement agreement. A key part of our mission is improving the quality of care received by patients living with HIV/AIDS and providing high quality education and training to health care professionals is an essential part of that effort.”

A copy of the OCR letter of finding and the settlement agreement, along with more information about OCR’s other civil rights enforcement activities, can be found here. In addition, an explanation of who is a qualified individual with a disability may be found here.

Source
HHS